FI95704C - Process for the preparation of novel therapeutically useful pyridine derivatives - Google Patents

Description

1 - 95704

A process for the preparation of new therapeutically useful pyridine derivatives

The invention relates to the preparation of novel substituted pyridine derivatives of the formula I and their pharmaceutically acceptable salts.

R1> ^ x X / (i> 10

R

wherein Z is oxygen or sulfur, R is hydrogen or C 1-6 alkyl and R 1 is halogen, amino, C 4-8 (cycloalkylalkyl), cyclopropylmethoxy, benzyloxy, morpholino, C 1-6 alkyl-substituted piperidino, C 1-8 acylamino , C 1-6 alkylamino, -O-R 2 or -S-R 2, wherein R 2 is straight-chain or branched C 1-6 -alkyl, straight-chain or branched C 2-6 -alkenyl, straight-chain or branched C 2-6 -alkynyl or R 2 is -R 3 -O-R 4 or -R 3 -O-R 4 -O-R 5, wherein R 3, R 4 and R 5 are independently C 1-6 alkyl. These compounds are muscarinic cholinergic agents.

Due to the general improved health status in the Western world, age-related diseases are now much more common than in the past and are likely to become more common in the future.

One of the symptoms associated with old age is a decrease in the functions associated with the content of consciousness. This symptom is particularly evident in a pathophysiological disease known as Alzheimer's disease. This disease is associated, and most likely, is caused by up to 90% degeneration of muscarinic-cholinergic neurons in the basal nucleus, which is part of the substantia innominata. These 35 neurons project the anterior lobe of the brain into the cortex and cerebral cortex and have a general stimulating effect on the functions of the forebrain and cerebral edema consciousness 2 - 95704, namely optical, association, consolidation and identification.

Alzheimer's disease is characterized by the fact that although cholinergic neurons degenerate, post-synaptic muscarinic receptors in the forebrain and cerebral edema still exist. Thus, muscarinic-cholinergic agonists are useful in the treatment of Alzheimer's disease as they improve the functional functions of the elderly.

Arecoline (methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is known to be such a cholinergic agonist (see formula A).

O

OH 3

However, the biological half-life of arecoline is very short and the difference between its central nervous system effect and peripheral muscarinic effects is small. In addition, arecoline is a relatively toxic compound. It is also known that 3-acetoxyquinuclidine is a muscarinic agonist (see formula B) 25 (2rV!

OF

However, the disadvantages of this compound are the same as with arecoline.

Thus, it is an object of the present invention to provide novel muscarinic-cholinergic compounds having structures and activity levels different from those described above.

The compounds of formula I are useful

In the treatment of Alzheimer's disease. The compounds are also useful analgesics from 3 to 95704 and can thus be used in the treatment of severe pain conditions.

In addition, the compounds of formula I can be used in the treatment of glaucoma.

5 All of the structures shown below are known to have affinity for muscarinic receptors, but only 3-alkyl-1,2,4-oxadiazol-5-yls (III and VII) and 3-alkyl-1,2,4-thiadiazol-5-yls ( IV and VIII) are agonists. 5-alkyl-1,2,4-thiadiazol-3-yl (V and 10 IX) and 5-alkyl-1,2,4-thiadiazol-3-yl (VI and X are antagonists a.

o * o * cF 'CH3 cÄ, ch3 cli3

III IV V VI

20 © <* sf * © *:

25 N

VII VIII IX x (where R = C 1-6 alkyl) A common feature of all the heterocycles with affinity for the muscarinic receptors shown is that the substituent (R) is always in the B-position with respect to the cyclic amine: a Br a Br

35 x / X = C or N

-v * -O 2 ° or s (XI) (XII) 4-95704

The difference between compounds XI and XII is the distribution of electrons in the heterocycle. That is, in Compound XI, the relative position of the double bonds with respect to the substituent is different from that in Compound XII.

Without wishing to be bound by any theory or mechanism, it is believed that this presumably contributes to the fact that the compounds of general formula XI are muscarinic agonists and the compounds of general formula XII are muscarinic antagonists.

10 It is therefore very surprising that the formula I

active compounds according to heterocyclic having a substituent at the α-position relative to the cyclic amine are highly efficient ester isosteres. There are no previously known α-substituted heterocycles that are ester-15 ri isosteres.

For example, 3- (3-subs.-1,2,5-thiadiazol-4-yl) -1,2,5,6-tetrahydro-1-methylpyridines (XIII) have been found to be very potent muscarinic agonists with M1- selectivity is better than ago-20 with a substituent at the B position.

Vn, (xiii) 25 cii

Also, not all α-substituted are ester isosteres. It is believed that the position of the double bond with respect to the substituent (R) is very important. If the electrostatic properties are different from those of the heterocyclic structure XIII, then the muscarinic agonist activity is significantly reduced. The compounds of general formula XIV are either antagonists or inactive.

35 5. 95704

R

V — χ X = C or N

^ W ^ Z * X Z = O or S

5 ci3 (XIV)

The compounds of general formula XV thus differ both structurally and biologically from the compounds of general formulas XI, XII and XIV.

/ v (x, Z X - C or N

15 II Z = 0 or S

CH3 (XV) The fact that compounds XIII are more suitable than compounds III to X for muscarinic receptors is believed to be due to the fact that substituent (R) can be larger and more lipophilic without loss of affinity and agonist activity. In fact, the best Mj selectivity is obtained with a C4-8 alkoxy group.

Compounds of formula I and their pharmaceutically acceptable salts may be prepared by alkylating a compound of formula N / / (II) (of 35 wherein Z and R 1 are as defined above) with an alkyl halide and reducing the resulting compound with hydride ions to give to give a compound of formula I, 6 to 95704 wherein R is C 1-6 alkyl, and if desired, to obtain a compound of formula I wherein R is C 1-3 alkyl is dealkylated to give a compound of formula I wherein R is hydrogen, and / or, if desired, converting the resulting compound into a pharmaceutically acceptable salt.

Examples of salts of the compounds of formula I include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate and the like, and other pharmaceutically acceptable inorganic and organic acid addition salts.

The pharmacological properties of the compounds of formula I can be demonstrated by determining their ability to specifically inhibit the binding of 3 H-oxotremorine-M (3 H-Oxo).

The 3H-Ocase is used as a marker for central nervous system muscarinic receptors (primarily receptor agonist sites). Three different places are marked with a 3H-0 period. The affinities of Ni-20 are 1.0, 20 and 3,000 nM, respectively. Only high and medium affinity sites are determined under the experimental conditions. The inhibitory effect of the compounds on binding to 3 H-Oxo indicates their affinity for muscarinic acetylcholine receptors.

All preparations are performed at 0-4 ° C, unless otherwise indicated. The fresh cortex (0.1-1 g) of male Wistar rats (150-250 g) is homogenized on an Ultra-Turrax homogenizer for 5-10 s in 10 ml of 20 mM Hepes at pH 7.4. The homogenizer is rinsed with 10 ml of pus-30 discipline and the combined suspensions are centrifuged for 15 min at 40,000 G. The pellet is washed 3 times with buffer. At each stage, the pellet is homogenized as above in 2 x 10 ml of buffer and centrifuged for 10 min at 40,000 G. The finally obtained pellet is homogenized in 20 mM Hepes, pH 7.4 (100 ml al-35 per gram of original tissue) and this homogenate is used for the binding experiment. To 0.5 ml aliquots add 25 μΐ of test solution and 25 μΐ of 3 H-Oxotremorine (1.0 nM final concentration 95704), mix and incubate for 30 min at 25 ° C. Non-specific binding is determined in a triplicate assay using arecoline (1 pg / ml, final concentration) as test substance. After incubation, 5 ml of ice-cold buffer is added to the samples and the samples are poured directly onto suction filtration on Whatman GF / C glass fiber filters and immediately washed twice with 5 ml of ice-cold buffer. The radioactivity to be filtered is determined with a conventional liquid scintillation counter. Specific binding is 10 total binding minus non-specific binding. The test compounds are dissolved in 10 ml of water (if necessary heated on a steam bath for less than 5 minutes) to a concentration of 2.2 mg / ml.

Inhibition of 25-75% specific binding must be obtained in order to calculate the IC50.

Test values are expressed as IC50 values (concentration of test compound in ng / ml, which inhibits 50% specific binding to 3H-Ox).

IC50 = (concentration of test compound) x - ng / ml 20 r C η o

- - 1 C

x J

where Cc is the specific binding of the control experiment and C is the specific binding of the test experiment (calculations 25 require normal mass-activity kinetics).

The experimental results obtained with the compounds of formula I are shown in Table 1 below.

TABLE 1 30

Inhibition of oxo-binding in vitro Compound No. (ng / ml) 1 1.5 2 0.4 35 3 0.2 4 0.5 8 95704 5 3.5 6 1.9 7 1.7 8 1.9 5 9 3.6 10 2.3 11 0.9 12 0.3 13 0.3 10 14 0.4 15 0.6 16 3.3 17 19.0 18 3.6 15 19 92 20 5.9 21 2, 4 22 0.4 23 0.3 20 24 0.4 25 12 26 0.4 27 0.8 28 1.3 25 29 0.6 30 0.4 31 0.7 32 1.4 33 1.0 30 34 1.0 35 0.6 36 0.3 37 6.3 38 7.4 35 39 4.1 9.1 - 95704 40 3.7 41 1.3 42 7.0 43 4.0 5 44 14 45 115 46 18 47 0.3 48 0.6 10 49 0.7 50 300 51 300 52 65 53 1.2 15 54 20 55 8 56 2.1 57 58 50 20 59 60 164 61 50 62 32 63 25 25 64 58 65 0.6 66 1.8 67 1.6 30 The following table shows the experimental results describing the ability of the compounds to displace 3 H-prencepine from rat brain homogenates. This assay is an accepted model for demonstrating affinity for muscarinic Mi receptors. Two 2-substituted 1,2,3-triazol-4-yl derivatives known from FI patent application 883,064 have been used as reference compounds.

10 - 95704 TABLE 2 EN 883 064 5 Compound No. ^ H-Pz, IC ^ q (nM) 70 55 72 790

10 Formula I

Compound No. 1 H-Pz, IC 2 (nM) 3 15 15 4 4.9 5 15 14 5.0 7 12 11 6.0 20 12 14 8 3.3 9 5.0 13 10 10 9.0 25 18 8 .0 15 20 21 11 22 8.3 23 6.7 30 24 18 26 5.7 27 3.7 28 7.1 29 8.7 35 31 6.6 11 - 95704 32 10 33 15 34 13 35 8, 9 5 37 7.0 47 4.0 48 1.55 65 18 66 2.4 10 67 7.0

The results show that the affinity of the new compounds of the formula I for muscarinic Mj receptors is considerably stronger than that of the known compounds mentioned.

The compounds of formula I, which may be in the form of pharmaceutically acceptable acid addition salts, together with customary additives, carriers or diluents, may be formulated into pharmaceutical compositions and dosage units and used as solids, such as tablets or filled capsules, or as liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with medication via oral or rectal suppositories, sterile injectable solutions 25 or parenteral administration the (including subcutaneous drug delivery). Such pharmaceutical compositions and unit dosage forms contain conventional ingredients in conventional proportions, as well as any other active compounds, and such unit dosage forms may contain any suitable effective muscarinic cholinergic agonist amount of active ingredient suitable for the intended daily dose. Thus, suitable representative unit dosage forms of tablets include tablets which 12. 95704 contain 10 mg of active ingredient per tablet or, more broadly, 1 to 100 mg of active ingredient.

The compounds of the formula I can thus be used for the formulation of conventional pharmaceutical preparations of galenic pharmacy, for example for administration to mammals, including humans, orally or parenterally.

Conventional diluents include pharmaceutically acceptable organic or inorganic carriers that are suitable for both parenteral and gastrointestinal administration and do not adversely react with the active compounds.

Examples of such carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethylated castor oil, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, dehydroxyl esters, pentaerythritol .

The pharmaceutical preparations can be sterilized and, if desired, mixed with excipients, emulsifiers, salts for adjusting the osmotic pressure, buffers and / or colorants and the like, provided that these do not adversely react with the active compounds.

Particularly suitable for parenteral use are injectable solutions or suspensions, preferably aqueous solutions, in which the active compound is dissolved in polyhydroxylated castor oil. Suitable dosage unit forms are ampoules.

Particularly suitable oral dosage forms are tablets or capsules containing talc and / or carbohydrate as carrier or binder, with lactose and / or corn starch and / or potato starch being the most preferred carrier. A syrup, elixir, etc., is a suitable dosage form in cases where a sweetened medium can be used.

In general, the compounds of formula I will be administered in unit dosage form containing from 1 to 100 mg of compound per unit dose in a pharmaceutically acceptable carrier.

The dose of a compound of formula I for mammals, e.g. humans, is 1 to 100 mg / day, preferably 10 to 70 mg / day.

A typical tablet that can be prepared by conventional tableting techniques has the following composition:

Active compound 5.0 mg Lactose 67.8 mg Ph. Eur.

Avicel® 31.5 mg

Amberlite® 1.0 mg

Magnesium stearate 0.25 mg Ph. Eur.

The high agonist activity of the compounds of formula 1 at muscarinic cholinergic receptors makes them particularly useful in the treatment of mammalian symptoms of impaired cerebral consciousness by administering the compounds in amounts that stimulate forebrain and cerebral edema. The important stimulatory activity of the compounds of the formula I comprises activity both against pathological-physiological disease, Alzheimer's disease and also against normal degeneration of brain functions.

Thus, the compounds of formula I may be administered as a medicament to a subject in need of stimulation of the forebrain and cerebral edema, e.g. a live animal, including a human, and if desired may also be in the form of pharmaceutically acceptable acid addition salts (such as hydrobromides, hydrochlorides or as sulphates, which in all cases are prepared in the usual or conventional manner, e.g. by co-evaporating a solution of the free base with an acid) and are usually co-administered with a pharmaceutically acceptable carrier or diluent, in particular and preferably in the form of an oral or rectal or parenteral external (including subcutaneous dosing), for administration in the form of te 10 hokkaan forebrain and hippocampus stimulating amount of an active agent, or at least the amount that effectively improves mammalian consciousness-related functions due to agonist activity at muscarinic-cholinergic receptors.

The compounds of formula I are also useful analgesics and can therefore be used in the treatment of severe pain conditions.

In addition, the compounds of formula I can be used in the treatment of glaucoma.

Suitable daily doses are from 1 to 100 mg, from 10 to 100 mg and in particular from 30 to 70 mg, depending on, for example, the usual route of administration, the pharmaceutical form, the disease to be treated, the recipient and the body weight and the experience of the prescribing physician or veterinarian.

The following examples illustrate the invention.

Example 1 Ä. 3- (4-chloro-l, 2,5-thiadiazol-3-yl) pyridine

To a solution of sulfur monochloride (2.4 mL, 30 mmol) in N, N-30 in dimethylformamide (5 mL) was slowly added α-amino-o- (3-pyridyl) acetonitrile (Archive der Pharmazie 289 (4) 1956)) (1.70 g, 10 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water is then added - 95704 (20 ml) and the aqueous phase is extracted with ether, the ether phase is discarded. A 50% KOH solution was added to the aqueous phase to a pH above 9. The aqueous phase was extracted several times with ether and the ether phases were dried and evaporated. Residue 5 was purified by chromatography on a SiO 2 column (eluent: ethyl: ethyl acetate / methyl chloride 1: 1). The title compound was obtained in 45% yield (880 mg). M +: 197.

B. 3- (4-Methoxy-1,2,5-thiadiazol-3-yl) pyridine To a solution of sodium (460 mg, 20 mmol) in methanol 10 (10 mL) was added 3- (4-chloro-1,2,5 -thiadiazol-3-yl) pyridine (750 mg, 3.8 mmol). The mixture was stirred at 50 ° C for 1 hour, then the mixture was evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic extracts were dried and evaporated to give the title compound as a residue which was crystallized from petroleum ether to give 630 mg (86%) of pure product.

C. 3- (4-Methoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.37 mL, 6 mmol) and 3- (4-methoxy-1,2,5,5-thiadiazol-3-yl) pyridine (500 mg, 2.5 mmol) in acetone (10 mL) was stirred at room temperature. 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 1.0 g (100%).

D. 1,2,5,6, -Tetrahydro-3- (4-methoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridine oxalate

Sodium borohydride (460 mg, 12 mmol) was added to a solution of 3- (4-methoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (1.0 g, 3 mmol) in ethanol (99.9- %, 20 ml) and the reaction mixture was stirred at room temperature for 30 hours. The solvent was evaporated and the residue was dissolved in water and extracted with methylene chloride. The dried organic phase was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized from the oxalate salt 95704 as acetone. Yield: 390 mg (m.p. 150 ° C; M +: 211; compound 1).

Example 2 A. 3- (4-Ethoxy-1,2,5-thiadiazol-3-yl) pyridine To a solution of sodium (440 mg, 17 mmol) in ethanol (10 mL) was added 3- (4-chloro-1,2-yl). (5-thiadiazol-3-yl) pyridine (540 mg, 3.3 mmol). The mixture was stirred at 40 ° C for 10 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give 520 mg (76%) of the title compound.

B. 3- (4-Ethoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide methyl iodide (0.3 mL, 5 mmol) and 3- (4-ethoxy-1,2,2, A mixture of 5-thiadiazol-3-yl) pyridine (520 mg, 2.5 mmol) in acetone (10 mL) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield 0.72 g (83%).

C. 3- (4-Ethoxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of 3- (4-ethoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.72 g, 2 mmol) in ethanol (99.9- %, 20 ml) and the reaction mixture was stirred at room temperature for 25 hours. The solvent was evaporated and the residue was dissolved in water and extracted with methylene chloride. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized from the oxalate salt-30 as methanol. Yield: 190 mg (m.p. 137 ° C; M *: 225; compound 2).

Example 3 A. 3- (4-Propoxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (440 mg, 17 mmol) in 1-propanol (35 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) -17570704 pyridine (650 mg, 3.3 mmol). The mixture was stirred at 50 ° C for 2 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic extracts were dried over water and extracted with methylene chloride. The combined organic extracts were dried and evaporated to give 700 mg (96%) of the title compound.

B. 3- (4-Propoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide Methyl iodide (0.37 mL, 6 mmol) and 3- (4-propoxy-1-yl). A mixture of 2,5-thiadiazol-3-yl) pyridine (700 mg, 3.1 mmol) in acetone (10 mL) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.98 g (88%).

15 C. 1,2,5,6-Tetrahydro-1-methyl-3- (4-propoxy-1,2,5-thiadiazol-3-yl) pyridine oxalate Sodium hydride (380 mg, 10 mmol) was added to 3- (4 -propoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridium iodide (980 mg, 2.7 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C. for an hour.

The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 440 mg (m.p. 148 ° C; M *: 239; compound 3).

Example 4 A. 3- (4-Butoxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (290 mg, 12.5 mmol) in n-butano-30 L (10 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (490 mg, 2.5 mmol). ). The mixture was stirred at 25 ° C for 18 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic extracts were dried and evaporated to give 580 mg (100%) of the title compound.

ie 95704 B. 3- (4-Butoxy-1,2,5-thiadiazol-3-yl) -1-methyl-pyridinium iodide

A mixture of methyl iodide (0.3 mL, 5 mmol) and 3- (4-butoxy-1,2,5-thiadiazol-3-yl) pyridine (580 mg, 2.5 mmol) in acetone (5 mL) was stirred at room temperature. 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.60 g (64%).

C. 3- (4-Butoxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (240 mg, 6.4 mmol) was added 3 - a solution of - (4-butoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.60 g, 1.6 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C for 1 hour. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 280 mg (m.p. 158 ° C; M +: 253; compound 4). 20 Example 5 Ά. 3- (4-isopropoxy-l, 2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (290 mg, 12.5 mmol) in isopropanol (10 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (490 mg, 2.5 mmol). The mixture was stirred at 25 ° C for 18 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic extracts were dried and evaporated to give 540 mg (98%) of the title compound.

B. 3- (4-Isopropoxy-1,2,5-thiadiazol-3-yl) -1-methylpyrididinium iodide

A mixture of methylene iodide (0.3 mL, 5 mmol) and 3- (4-isopropoxy-1,2,5-thiadiazol-3-yl) pyridine (540 mg, 2.4 mmol) in acetone (5 mL) was stirred at room temperature. at a temperature of 18 hours. The title compound precipitated from solution 35 and was collected by filtration. Yield: 0.68 g (77%).

19 95704 C. 1,2,5,6-Tetrahydro-3- (4-isopropoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridine oxalate

Sodium borohydride (280 mg, 7.2 mmol) was added to a solution of 3- (4-isopropoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridin-5-sodium iodide (650 mg, 1.8 mmol) in ethanol (99 .9%, 20 ml) and the reaction mixture was stirred at 0 ° C for 1 hour. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 280 mg (m.p. 164 ° C; M +: 239; compound 5). Example 6 A. 3- (4-Pentyloxy-1,2,5-thiadiazol-3-yl) pyridine To a solution of sodium (230 mg, 10 mmol) in 1-pentanol (20 mL) was added 3- (4-chloro -1,2,5-thiadiazol-3-yl) -pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50 ° C for 3 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4-Pentyloxy-1,2,5-thiadiazol-3-yl) -1-methyl-1-pyridinium iodide

A mixture of methyl iodide (0.3 mL, 5 mmol) and 3- (4-pentyloxy-2S-1,2,5-thiadiazol-3-yl) pyridine (620 mg, 2.5 mmol) in acetone (5 mL) was stirred. at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.81 g (84%).

C. 1,2,5,6-Tetrahydro-1-methyl-3- (4-pentyloxy-1,2,5-thiadiazol-3-yl) pyridine oxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of 3- (4-pentyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.81 g, 2 mmol) in ethanol (99.9- %, 20 ml) and the reaction mixture was stirred at 0 ° C for 35 hours. The solvent was evaporated and the residue was dissolved in water (95704) and extracted with ether. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1).

The title compound was crystallized as the oxalate salt from acetone.

Yield: 220 mg (m.p. 150 ° C; M +: 267; compound 6).

Example 7 A. 3- (4-Isobutoxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (230 mg, 10 mmol) in isobutanol (10 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) -10 pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50 ° C for 3 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4-Isobutoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methylene iodide (0.6 mL, 10 mmol) and 3- (4-isobutoxy-1,2,5-thiadiazol-3-yl) pyridine (588 mg, 2.5 mmol) in acetone (5 mL) was stirred at room temperature. 20 modes for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.88 g (87%).

C. 1,2,5,6-Tetrahydro-3- (4-isobutoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridine oxalate Sodium borohydride (160 mg, 4.3 mmol) was added. - (4-isobutoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.82 g, 2.2 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C for 1 hour. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 400 mg (m.p. 135 ° C; M +: 253? Compound).

2i 95704

Example 8 A. 3- (4-Isopentyloxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (230 mg, 10 mmol) in isopentanol-5 L (20 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (490 mg, 2.5 mmol) and the mixture was stirred at 50 ° C. for 2 hours, then the mixture was evaporated, the residue was dissolved in water and extracted with ether, and the combined organic extracts were dried and evaporated to give the desired compound.

B. 3- (4-Isopentyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 10 mmol) and 3- (4-isopentyloxy-1,2,5-thiadiazol-3-yl) pyridine (622 mg, 2.5 mmol) in acetone (5 mL) was stirred at room temperature. mode for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.78 g (81%).

C. 1,2,5,6-Tetrahydro-3- (4-isopentyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridine oxalate Sodium borohydride (150 mg, 4 mmol) was added 3- ( To a solution of 4-isopentyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (780 mg, 2 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C: for one hour. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 350 mg (m.p. 152 ° C; M +: 267; compound 8). Example 9 A. 3- (4-Hexyloxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (230 mg, 10 mmol) in 1-hexanol (15 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (490 mg, 2.5 mmol). The mixture was stirred at 35-50 ° C for 2 hours, then the mixture was evaporated. Residue 22 95704 was dissolved in water and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4-Hexyloxy-1,2,5-thiadiazol-3-yl) -1-methyl-lipyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and 3- (4-hexyloxy-1,2,5-thiadiazol-3-yl) pyridine (658 mg, 2.5 mmol) in acetone (5 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.81 g (80%).

C. 3- (4-Hexyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (230 mg, 6 mmol) was added to 3- (4-hexyloxy). To a solution of -1,2,5-thiadiazol-3-yl) -1-methylpyridin-15-iodine iodide (810 mg, 2 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 350 mg (m.p. 148 ° C; M +: 281; compound 9).

Example 10 A. 3- (4-Benzyloxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (490 mg, 2.5 mmol) in benzyl alcohol (15 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50-50 ° C for 2 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.

23 95704 B. 3- (4-Benzyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and 3- (4-benzyloxy-1,2,5-thiadiazol-3-yl) pyridine (673 mg, 2.5 mmol) in acetone (5 mL ) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.75 g (73%).

C. 3- (4-Benzyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (230 mg, 6 mmol) was added 3- (4- benzyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (750 mg, 1.8 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C: for one hour. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 340 mg (m.p. 149 ° C; M +: 287; compound 10). Example 11 A. 3- (4- (3-Butenyloxy) -1,2,5-thiadiazol-3-yl) pyridine 3-Buten-1-ol (540 mg, 7.5 mmol) and sodium hydride To a solution of 3- (4 mg, 7.5 mmol) in anhydrous tetrahydro-furan was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) -pyridine (490 mg), 2.5 mmol) in anhydrous tetra-hydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give 650 mg of the title compound.

B. 3- (4- (3-Butenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and 3- (4- (3-butynyloxy) -1,2,5-thiadiazol-3-yl) pyridine (583 mg, 2.5 mmol). in acetone (5 ml) was stirred at room temperature 95704 for 24 hours. The title compound precipitated from solution and was collected by filtration. Yield: 890 mg (96%).

C. 3- (4- (3-Butenyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium hydride (210 mg, 5.5 mmol) was added to a solution of 3- (4- (3-butenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (1.03 g, 2.8 mmol) in ethanol (99.9%: and 20 ml) and the reaction mixture was stirred at 0 ° C for 1 hour. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by column chromatography over SiO 2 (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 380 mg (m.p. 141 ° C; M +: 251; compound 11).

Example 12 A. 3- (4- (2-Butynyloxy) -1,2,5-thiadiazol-3-yl) pyridine 2-Butyn-1-ol (530 mg, 7.5 mmol) and sodium hydride-20 To a solution of 3- (4 mg, 7.5 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) -pyridine (490 mg, 2.5 mmol) in anhydrous tetrahydrofuran. rofuraanissa. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (2-Butynyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and 3- (4- (2-butynyloxy) -1,2,5-thiadiazol-2-yl) pyridine (578 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.88 g (95%).

25 95704 C. 3- (4- (2-butynyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (180 mg, 4.7 mmol) was added 3- (4- (2-butynyloxy) -1,2,5-thiadiazol-3-yl) -1-methyl-5-pyridium iodide (0.88 g, 2.34 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C for 1 h. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 140 mg (m.p. 158 ° C; M +: 249; compound 12).

Example 13 15 A. 3- (4-Propargyloxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of propargyl alcohol (420 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in anhydrous tetrahydrofuran was added 3- (4-chloro-1,2,5-thiadiazol-3-20 yl) pyridine. (490 mg, 2.5 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give 530 mg (98%) of the title compound.

25 B. 3- (4-Propargyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.45 mL, 7.2 mmol) and 3- (4-propargyloxy-1,2,5-thiadiazol-3-yl) pyridine (430 mg, 2.4 mmol) in acetone (5 mL) was stirred at room temperature. heat-30 mode for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.58 g (67%).

C. 1,2,5,6-Tetrahydro-1-methyl-3- (4-propargyloxy-1,2,5-thiadiazole-3-66-pyridine oxalate Sodium borohydride (230 mg, 6 mmol) was added 3-35 (4-propargyloxy To a solution of -1,2,5-thiadiazol-3-yl) -1-methylpyrrolidin-955 dinium iodide (0.68 g, 1.9 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate, the dry organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). Yield: 200 mg (m.p. 155 ° C; M +: 235; compound 13).

10 Example 14 Ä. 3- (4-Cyclopropylmethoxy-1,2,5-thiadiazol-3-yl) -pyridine

To a solution of cyclopropylcarbinol (360 mg, 5 mmol) and sodium hydride (110 mg, 5 mmol) in anhydrous tetrahydrofuran was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (490 mg, 2.5 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give 400 mg (69%) of the title compound.

B. 3- (4-Cyclopropylmethoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridium iodide

A mixture of methyl iodide (0.25 mL, 4 mmol) and 3- (4-cyclopropylmethoxy-1,2,5-thiadiazol-3-yl) pyridine (400 mg, 1.7 mmol) in acetone (5 mL) was stirred at room temperature. 36 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.41 g (65%).

C. 3- (4-Cyclopropylmethoxy-1,2,5-thiadiazol-3-yl) -2,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (170 mg, 4.4 mmol) was added to a solution of 3- (4-cyclopropylmethoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridium iodide (410 mg, 1.1 mmol) in ethanol (99, 9%, 20 ml) and the reaction mixture was stirred at 35 ° C for 1 hour. The solvent was evaporated and the residue 95704 27 was dissolved in water and extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by column chromatography over SiO 2 (eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate-5 salt from acetone. Yield: 130 mg (m.p. 153 ° C; M +: 251; compound 14).

Example 15 A. 3- (4-Chloro-1,2,5-thiadiazol-3-yl) -1-methylpyridium iodide Methyl iodide (4.25 mL, 30 mmol) and 3- (4-chloro-1, A solution of 2,5-thiadiazol-3-yl) pyridine (1.98 g, 10 mmol) in acetone (10 mL) was stirred at room temperature for 16 hours. The title compound precipitated from solution by filtration. Yield: 3.40 g (100%).

B. 3- (4-Chloro-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate To a suspension of sodium borohydride (330 mg, 8.6 mmol) in ethanol (20 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (1.46 g, 4.3 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography on a SiO 2 column (eluent: ethyl acetate / methanol 4: 1). Yield: 880 mg (95%). Crystallization from oxalic acid from acetone gave the title compound m.p.

124 ° C; M *: 215 and 217; compound).

C. 1,2,5,6-Tetrahydro-3- (4-methoxyethoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridine oxalate

To a solution of sodium (120 mg, 5 mmol) in 2-methoxyethanol (10 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro- 1-methylpyridine oxalate (310 mg, 1 mmol). The mixture was stirred at 50 ° C for 18 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic extracts were dried and evaporated. The title compound was crystallized as the oxalate salt from acetone. Yield: 270 mg (m.p.

152.1 ° C; M +: 253; compound 15).

D. 3- (4-Chloro-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydropyridine hydrochloride 3- (4-chloro-1,2,5-thiadiazol-3 -yl) -1,2,5,6-tetrahydro-1-methylpyridine (670 mg, 3.1 mmol) in 1,2-dichloroethane (20 mL) was added 1-chloromethyl chloroformate (20 mL) at 0 ° C. 440 mg, 3.1 mmol) in 1,2-dichloroethane. The reaction mixture was heated at 40 ° C for 2 to 10 hours, then evaporated. The residue was dissolved in methanol and the solution was heated to reflux for one hour. The solution was allowed to cool to room temperature, the separated precipitate was collected by filtration. Yield: 320 mg (41%) (m.p. 224 ° C; M +: 201 and 203; compound 17).

E. 3- (4-butoxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydropyridine oxalate

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (15 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydropyridine hydrochloride. (240 mg, 1 mmol). The mixture was stirred at 50 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to give an oil (200 mg). Crystallization as the oxalate salt from acetone gave the title compound. Yield: 170 mg (52%) (m.p. 173-174 ° C; M +: 239; compound 18).

Example 16 A. 3- (4-Chloro-1,2,5-thiadiazol-3-yl) -1-ethylpyridinium iodide

A solution of ethyl iodide (22.65 g, 17 mmol) and 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (1.13 g, 5.7 mmol) in acetone (15 mL) was stirred. At 40 ° C for 16 hours. The title compound precipitated from solution and was collected by filtration. Yield: 510 mg (26%).

29 95704 B-3- (4-chloro-1,2,5-thiadiazol-3-yl) -1-ethyl-1,2,5,6-tetrahydropyridine oxalate

To a suspension of sodium borohydride (170 mg, 4.5 mmol) in ethanol (10 mL) at 0 ° C was added 3- (4-chloro-1,2,5-5 thiadiazol-3-yl) -1-ethylpyridinium iodide (510 mg, 1 , 5 mmol). The reaction mixture was stirred at 0 ° C for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (eluent: ethyl acetate-10t / methanol 4: 1). Crystallization from oxalic acid from acetone gave the title compound. Yield: 70 mg (m.p. 143 ° C; M +: 229 and 231; compound 19).

Example 17 A. 3- (4-Ethoxy-1,2,5-thiadiazol-3-yl) -1-ethylpyridinium iodide

A solution of ethyl iodide (2.03 g, 13 mmol) and 3- (4-ethoxy-1,2,5-thiadiazol-3-yl) pyridine (0.90 g, 4.3 mmol) in acetone (4 mL) was stirred at 40 ° C. At 16 ° C. The title compound precipitated from solution and was taken up by filtration of tal-20 tea. Yield: 1.34 g (86%).

B. 3- (4-Ethoxy-1,2,5-thiadiazol-3-yl) -1-ethyl-1,2,5,6-tetrahydropyridine oxalate To a suspension of sodium borohydride (410 mg, 10.8 mmol) in ethanol (10 mL) was added 0 ° At C 3- (4-ethoxy-1,2,5-thiadiazol-3-yl) -1-ethylpyridinium iodide (1.32 g, 3.6 mmol). The reaction mixture was stirred at 0 ° C for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (eluent: ethyl acetate / methanol 4: 1). Crystallization from oxalic acid in acetone gave 0.49 g of the title compound (m.p.

120-122 ° C; M +: 239; compound 20).

30 95704

Example 18 3- (4-Heptyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

To a solution of sodium (120 mg, 5 mmol) in 1-heptanol 5 (10 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-yl. methyl pyridine oxalate (310 mg, 1 mmol). The mixture was stirred at 50 ° C for 18 hours. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to give an oil. Crystallization as the oxalate salt from acetone gave the title compound. Yield: 270 mg (70%) (m.p. 152 ° C; M +: 295; compound 21).

Example 19 A. 3- (4- (3-Pentyloxy) -1,2,5-thiadiazol-3-yl) pyridine 3-pentyn-1-ol (750 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (3-Pentynyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.6 mL, 9 mmol) and 3- (4- (3-pentynyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (10 mL) was stirred at room temperature. 18 hours. The title compound precipitated from solution and was recovered by filtration. Yield: 0.68 g (59%).

C. 3- (4- (3-Pentynyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (150 mg, 4 mmol) was added 3- To a solution of (4- (3-pentynyloxy) -1,2,5-thiadiazol-3-yl) -1-methyl-3-pyridinium iodide (0.68 g, 1.7 mmol) in ethanol 3i 95704 (99.9%: inen, 15 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 240 mg (mp 166-1670 ° C; M +: 263; compound 22).

Example 20 10 Ä. 3- (4- (4-pentenyloxy) -1,2,5-thiadiazol-3-yl) pyridine 4-penten-1-ol (640 mg, 7.5 mmol) and sodium hydride (260 mg, To a solution of 7.5 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) -1-pyridine (490 mg, 2.5 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (4-pentyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and 3- (4- (4-Pentynyloxy) -1,2,5-thiadiazol-3-yl) pyridine (2.5 mmol) in acetone (10 mL ) was stirred at room temperature for 25 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.67 g (69%).

C. 3- (4- (4-Pentyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (150 mg, 4 mmol) was added 3- 30 (4- (4-pentyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.67 g, 1.7 mmol) in ethanol (99.9%, 15 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dry ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 150 mg (m.p. 141-142 ° C; M +: 265; compound 23).

Example 21 A. 3- (4- (2-propenyloxy) -1,2,5-thiadiazol-3-yl) pyridine

To a solution of allyl alcohol (650 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (2-Propenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.4 mL, 6 mmol) and 3- (4- (2-propenyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) was stirred at room temperature. hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.96 g (88%).

C. 3- (4- (2-Propenyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (210 mg, 5.5 mmol ) was added to a solution of 3- (4- (2-propenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.96 g, 2.6 mmol) in ethanol (99.9% : inen, 25 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dry ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 270 mg (m.p. 136-137 ° C; M +: 35 237; compound 24).

33 95704

Example 22 A. 3- (4-Octyloxy-1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (350 mg, 15 mmol) in 1-octanol (10 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) -pyridine (590 mg, 3 mmol). The mixture was stirred at 50 ° C for one hour. The mixture was evaporated and the residue was dissolved in water and extracted with methylene chloride. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4-Octyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1 mL, 15 mmol) and 3- (4-octyloxy-1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) was stirred at room temperature for 18 hours.

The title compound precipitated from solution and was collected by filtration. Yield: 0.81 g (62%).

C. 3- (4-Octyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (210 mg, 5.6 mmol) was added to a solution of 3- (4-octyloxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.81 g, 1.87 mmol) in ethanol. (99.9%, 10 mL). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dry ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 330 mg (m.p. 144-145 ° C; M +: 309; compound 25).

Example 23 A. 3- (4- (3-Hexynyloxy) -1,2,5-thiadiazol-3-yl) pyridine 3-Hexyn-1-ol (880 mg, 9 mmol) and sodium hydride (310 mg (9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyrid-34570704 didine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (3-Hexynyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1 mL, 15 mmol) and 3- (4- (3-hexynyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) was stirred at room temperature. hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.85 g (71%).

C. 3- (4- (3-Hexynyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (190 mg, 5 mmol) was added 3 - (4- (3-hexynyloxy) -1,2,5-thiadiazol-3-yl) -1-methyl-pyridinium iodide (0.85 g, 2.1 mmol) in ethanol (99.9%, 10 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dry ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 350 mg (m.p. 174-175 ° C; M +: 25 277; compound 26).

Example 24 Ä. 3- (4- (3-methyl-2-butenyloxy) -1,2,5-thiadiazol-3-yl) pyridine 3-methyl-2-buten-1-ol (780 mg, 9 mmol) and nat-30 To a solution of rium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 20 minutes. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (3-Methyl-2-butenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide 5 Methyl iodide (1 mL, 15 mmol) and 3 A mixture of - (4- (3-methyl-2-butenyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (3 ml) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.92 g (79%). 10 C. 3- (4- (3-methyl-2-butenyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (220 mg, 6 mmol) was added as 3- (4- (3-methyl-2-butenyloxy) -1,2,5-thiadiazol-3-yl) -1-15 methylpyridinium iodide (0.92 g). , 2.3 mmol) in ethanol (99.9%, 15 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 380 mg (m.p. 150-151 ° C; M +: 265; compound 27).

Example 25 A. 3- (4- (3-Butenyl-2-oxy) -1,2,5-thiadiazol-3-yl) -pyridine 3-Buten-2-ol (650 mg, 9 mmol) and sodium hydride To a solution of (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridin-30 (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 18 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

36 95704 B. 3- (4- (3-Butenyl-2-oxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1 mL, 15 mmol) and 3- (4- (3-butenyl-2-oxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (3 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.73 g (65%).

C. 3- (4- (3-Butenyl-2-oxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (190 mg, 5 mmol) was added to a solution of 3- (4- (3-butenyl-2-oxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.73 g, 1.9 mmol) in ethanol ( 99.9%, 15 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 270 mg (m.p. 134-135 ° C; M +: 251; compound 28).

Example 26 A. 3- (4- (4-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) pyridine 4-Hexen-1-ol (900 mg, 9 mmol) and sodium hydride 25 (310 mg (9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (4-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1 mL, 15 mmol) and 3- (4- (4-hex-35-senyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) was stirred at room temperature. at a temperature of 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.54 g (45%) of C. 3- (4- (4-hexenyloxy) -1,2,5-thiadiazol-3-yl) -5,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of 3- (4- (4-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.54 g, 1.3 mmol). in ethanol (99.9%, 15 mL). The reaction mixture was stirred at 10-10 ° C for 0.5 hours. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 190 mg (m.p. 151-152 ° C; M +: 279; compound 29).

Example 27 A. Trans-3- (4- (3-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) pyridine Trans-3-hexen-1-ol (900 mg, 9 mmol) and sodium To a solution of the hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 25 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. Trans-3- (4- (3-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide Methyl iodide (1 mL, 15 mmol) and trans-3- (4- (3 - a mixture of hexenyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.90 g (75%).

38 95704 C. Trans-3- (4- (3-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (190 μg, 5 mmol) was added 3-5 (4- (3-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.90 g, 2.2 mmol). to a solution in ethanol (99.9%, 15 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 420 mg (m.p. 163-164 ° C; M +: 279; compound 30).

Example 28 A. Cis-3- (4- (2-pentyloxy) -1,2,5-thiadiazol-3-yl) pyridine

To a solution of cis-2-penten-1-ol (780 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added 3- (4-chloro-1,2,5-thiadiazol-3 - yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour and evaporated to give the title compound.

B. Cis-3- (4- (2-pentyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1 mL, 15 mmol) and cis-3- (4- (2-pentynyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) was stirred at room temperature. 30 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.53 g (46%).

39 95704 C. Cis-3- (4- (2-pentyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (150 mg, 4 mmol) was added to cis-3- (4- (2-pentyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.53 g, 1.3 mmol). to a solution in ethanol (99.9%, 15 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 210 mg (m.p. 143-144 ° C; M +: 265; compound 31).

15 Example 29 Ä. Cis-3- (4- (2-hexenyloxy) -1,2,5-thiadiazol-3-yl) pyridine

To a solution of cis-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydro-furan was added 3- (4-chloro-1,2,5-thiadiazol-3 -yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. Cis-3- (4- (2-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and cis-3- (4- (2-hexyloxy) -1,2,5-thiadiazol-3-yl) pyridine in acetone (4 mL) (4 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration.

40 95704 C. Cis-3- (4- (2-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of cis-3- (4- (2-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.6 g, 1 mmol) in ethanol. (99.9%, 20 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield 150 mg (m.p. 122-123 ° C; M ": 279; compound 32).

15 Example 30 Ä. 3- (4- (5-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) pyridine in a solution of 5-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran, a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran was added. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (5-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and 3- (4- (5-hexenyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.75 g (62%).

4i 95704 C. 3- (4- (5-Hexynyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (150 mg, 4 mmol) was added 3- (4- (5-hexyloxy) -1,2,5-thiadiazol-3-yl) -1-methyl-5-pyryridinium iodide (0.75 g, 1.8 mmol). to a solution in ethanol (99.9%, 20 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 250 mg (m.p. 137-138 ° C; M +: 279; compound 33).

Example 31 A. Cis-3- (4- (3-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) pyridine

To a solution of cis-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added 3- (4-chloro-1,2,5-thiadiazol-3- yl) -20 pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

25 Cis-3- (4- (3-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and cis-3- (4- (3-hexenyloxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) was stirred. at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 0.9 g (46%).

42 95704 C. Cis-3- (4- (3-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (230 mg, 6 mmol) was added to cis-3- (4- (3-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.90 g, 2.2 mmol). to a solution in ethanol (99.9%, 15 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 300 mg (m.p. 149-150 ° C; M *: 279; compound 34).

Example 32 A. Trans-3- (4- (2-Hexyenyloxy) -1,2,5-thiadiazol-3-yl) pyridine

To a solution of trans-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added 3- (4-chloro-1,2,5-thiadiazol-3 -yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. Trans-3- (4- (2-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 7.5 mmol) and trans-3- (4- (2-hexenyloxy) -1,2,5-thiadiazol-3-yl) pyridine 30 (3 mmol) in acetone (5 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 1.09 g (90%).

it r - * # · * MK »'» 4 «i; 95704 43 C. Trans-3- (4- (2-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (270 mg, 4 mmol) was added to trans-3- (4- (2-hexenyloxy) -1,2,5-thiadiazol-3-yl) -1-roethylpyridinium iodide (1.09 g, 2.7 mmol). to a solution in ethanol (99.9%, 20 mL). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 400 mg (m.p. 130-131 ° C; M +: 279; compound 35).

Example 33 A. 3- (1,2,5-Thiadiazol-3-yl) pyridine To a solution of L-butanethiol (2.7 g, 30 mmol) and sodium hydride (1.2 g, 30 mmol) in anhydrous tetrahydrofuran was added 3- A solution of (4-chloro-1,2,5-thiadiazol-3-yl) pyridin-20 (1.2 g, 6 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at -10 ° C for 0.5 h. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated, the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methylene chloride 1: 1) to give the title compound.

B. 3- (1,2,5-Thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1 mL, 15 mmol) and 3- (1,2,5-thiadiaz-30-sol-3-yl) pyridine (6 mmol) in acetone (5 mL) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 1.2 g (74%).

95704 44 C. 3- (1,2,5-Thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of 3- (1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide 5 (1.2 g, 4.4 mmol) in ethanol (99.9% , 20 ml). The reaction mixture was stirred at -10 ° C for 0.5 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 430 mg (m.p. 189-190 ° C; M +: 181 compound 36).

Example 34 1,2,5,6-Tetrahydro-3- (3-hexyloxy-1,2,5-thiadiaz-15-sol-3-yl) pyridine oxalate 3- (4-hexyloxy-1,2,5-thiadiazole To a solution of 3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (0.70 g, 2.4 mmol) in 1,2-dichloroethane (20 mL) at 0 ° C was added 1-chloromethyl chloroformate (0, 35 g, 2.4 mmol) in a solution of 1,2-dichloroethane. The reaction mixture was heated at 40 ° C for 2 hours, then evaporated. The residue was dissolved in methanol and the solution was heated to reflux for 1 hour and the solution was evaporated. The residue was dissolved in dilute sodium hydroxide solution and extracted with ether. The combined ether phases were dried and evaporated. Crystallization of the oxalate salt from acetone gave the title compound in 72% yield (620 mg) (mp 157-159 ° C; M +: 267: compound 37).

Example 35 A. 3- (4- (2- (2-methoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) pyridine

To a solution of sodium (210 mg, 9 mmol) in 2- (2-methoxyethoxy) ethanol (10 mL) was added 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol). The mixture was stirred at 50 ° C for 4 hours. The mixture was evaporated and the residue 95704 45 was dissolved in water and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4- (2- (2-methoxyethoxy) ethoxy) -1,2,5-thiadiazol-5-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 9 mmol) and 3- (4- (2-2 (2-methoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (10 mL ) was stirred at room temperature for 18 hours. The title compound precipitated from solution 10 and was collected by filtration. Yield: 0.76 g (60%).

C. 3- (4- (2- (2-methoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (150 mg, 4 mmol) was added 3-15 (4- (2- (2-methoxyethoxy) ethoxy-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (0.76 g, 1.8 mmol) in ethanol (99.9%, 20 ml) The reaction mixture was stirred for 1 hour at -10 [deg.] C. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. (SiO 2, eluent: ethyl acetate / methanol 4: 1) The title compound was crystallized as the oxalate salt in acetone Yield: 70 mg (mp 142-143 ° C; M +: 299 compound 38).

Example 36 A. 3- (4- (3-Ethoxy-1-propoxy) -1,2,5-thiadiazol-3-yl) pyridine 3-Ethoxy-1-propanol (940 mg, 9 mmol) and sodium To a solution of the hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

46 9 5 7 0 4 B. 3- (4-3-Ethoxy-1-propoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 9 mmol) and 3- (4- (3-ethoxy-1-propoxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration.

C. 3- (4- (3-Ethoxy-1-propoxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine-10 oxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of 3- (4- (3-ethoxy-1-propoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyrididinium iodide (3 mmol) in ethanol (99 mmol). .9%, 15 ml). The reaction mixture was stirred at -10 ° C for 15 hours. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 210 mg (m.p. 149-150 ° C; M *: 283 compound 39). Example 37 Ä. 3- (4- (2-ethoxyethoxy) -1,2,5-thiadiazol-3-yl) pyridine in a solution of 2-ethoxyethanol (1.08 g, 12 mmol) and sodium hydride-25 (410, 12 mmol) in anhydrous tetrahydrofuran, a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (790 mg, 4 mmol) in anhydrous tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (2-Ethoxyethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 9 mmol) and 3- (4- (2-ethoxy-35-ethoxy) -1,2,5-thiadiazol-3-yl) pyridine (4 mmol) in acetone (95 mL) (95 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 1.45 g (92%).

C. 3- (4- (2-ethoxyethoxy) -1,2,5-thiadiazol-3-yl) -5,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (350 mg, 9 mmol) was added to a solution of 3- (4- (2-ethoxyethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (1.45 g, 3.7 mmol). in ethanol (99.9%, 15 mL), the reaction mixture was stirred at -10 ° C for 10 hours. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2), eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate-15 salt from acetone. Yield: 640 mg (m.p. 153-156 ° C; M +: 269; compound 40).

Example 38 Ä. 3- (4- (2-butoxyethoxy) -1,2,5-thiadiazol-3-yl) pyridine 2-butoxyethanol (1.06 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) To a solution of anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (2-Butoxyethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide Methyl iodide (0.5 mL, 9 mmol) and 3- (4- (2- a mixture of butoxyethoxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (4 ml) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 1.07 g (85%).

95704 48 C. 3- (4- (2-butoxyethoxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (230 mg, 6 mmol) was added 3- (4- (2-butoxyethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridium-5-ridinium iodide (1.07 g, 2.5 mmol). to a solution in ethanol (99.9%, 20 mL). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 490 mg (m.p. 152-153 ° C; MM +: 297 compound 41).

Example 39 A. 3- (4- (2- (2-butoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) pyridine 2- (2-butoxyethoxy) ethanol (1.46 g, 9 mmol) ) and a solution of sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. Water was added to the mixture and the mixture was extracted with ether, the ether phase dried and evaporated to give the title compound.

B. 3- (4- (2- (2-butoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 9 mmol) and 3- (4- (2- (2-butoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone (5 mL) stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration.

49 95704 C. 3- (4- (2- (2-butoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of m3-5 (4- (2- (2-butoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (3 mmol) in ethanol (99 %, 20 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate-10thate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 340 mg (m.p. 90-91 ° C; M +: 341 compound 42).

Example 40 A. 3- (4- (2- (2-ethoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) pyridine 2- (2-ethoxyethoxy) ethanol (1.21 g, 9 mmol ) and a solution of sodium hydride (310 mg, 9 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in anhydrous tetrahydrofuran. in tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. 3- (4- (2- (2-ethoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 9 mmol) and 3- (4- (2- (2-ethoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) pyridine (3 mmol) in acetone ( 5 ml) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration.

mp 95704 C. 3- (4- (2- (2-ethoxyoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of 3-5 (4- (2- (2-ethoxyethoxy) ethoxy) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (3 mmol) in ethanol (99 .9%, 20 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dry ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 290 mg (m.p. 115-116 ° C; M *: 313 compound 43).

Example 41 A. 3- (4- (4-methylpiperidino) -1,2,5-thiadiazol-3-yl) pyridine 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine ( 10.80 g, 4 mmol) and a solution of 4-methylpiperidine (1.96 g, 20 mmol) in dimethylformamide (10 mL) was heated at 100 ° C for 3 h. The mixture was evaporated and water was added to the residue and the mixture was extracted with ether. The combined and dried organic extracts were evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methylene chloride 1: 2). Yield: 0.8 g (77%).

B. 3- (4- (4-methylpiperidino) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (0.5 mL, 8 mmol) and 3- (4- (4-methyl-piperidino) -1,2,5-thiadiazol-3-yl) pyridine (0.8 g, 3.1 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 1.14 g (92%).

51 95704 C. 3- (4- (4-methylpiperidino) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (270 mg, 7 mmol) was added 3-5 (4- (4-methylpiperidino) -1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (1.14 g, 2.8 mmol). to a solution in ethanol (99.9%, 20 mL). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dry ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 450 mg (m.p. 106-107 ° C; M +: 278 compound 44).

Example 42 A. 3- (4-Morpholino-1,2,5-thiadiazol-3-yl) pyridine 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (0.59 g , 3 nunol) and a solution of morpholine (1.3 g, 15 mmol) in dimethylformamide (5 mL) was heated at 100 ° C for 3 h. The mixture was evaporated and water was added to the residue and the mixture was extracted with ether. The combined and dried organic extracts were evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methylene chloride 1: 1). Yield: 0.68 g (91%).

B. 3- (4-Morpholino-1,2,5-thiadiazol-3-yl) -1-methyl-pyridinium iodide

A mixture of methyl iodide (0.5 mL, 8 mmol) and 3- (4-morpholino-1,2,5-thiadiazol-3-yl) pyridine (680 mg, 2.7 mmol) in acetone (5 mL) was stirred at room temperature. 18 hours. The title compound precipitated from solution and was collected by filtration. Yield: 1.0 g (94%).

52 95704 C. 3- (4-Morpholino-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of 3- (4-morpholino-1,2,5-thiadiazol-3-yl) -1-methylpyridinium-5-iodide (1.53 g, 39 mmol) in ethanol (99.9 -%, 30 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1).

The title compound was crystallized as the oxalate salt from acetone. Yield: 470 mg (m.p. 177-178 ° C; M +: 266 compound 45). Example 43 A. 3- (4-Hexylamino-1,2,5-thiadiazol-3-yl) pyridine 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridine (0, A solution of 59 g, 3 mmol) and hexylamine (1.52 g, 15 mmol) in dimethyl sulfoxide (5 mL) was heated at 100 ° C for 48 h. The mixture was evaporated, water was added to the residue and the mixture was extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4-Hexylamino-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide Methyl iodide (0.6 mL, 9.6 mmol) and 3- (4-hexylamino) A mixture of 1,2,5-thiadiazol-3-yl) pyridine (3.2 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours, then the mixture was evaporated.

C. 3- (4-Hexylamino-1,2,5-thiadiazol-3-yl) -2,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of 3- (4-hexylamino-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (4.2 mmol) in ethanol (99.9%). , 25 ml). The reaction mixture was stirred at -10 ° C for 1 hour.

The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2 / eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 5,490 mg (m.p. 102-103 ° C; M *: 280 compound 46).

Example 44 A. 3- (4-Propylthio-1,2,5-thiadiazol-3-yl) pyridine

Sodium hydrogen sulfide (220 mg, 3 mmol) was added over 30 minutes at room temperature to a solution of 3- (4-chloro-1,2,5-10 thiadiazol-3-yl) pyridine (0.59 g, 3 mmol) in dimethylformamide (20 mL). . Potassium carbonate (1.24 g, 9 mmol) and iodopropane (0.76 g, 4.5 mmol) were added to the mixture. The reaction mixture was stirred at room temperature for 30 minutes. Water was added to the mixture, and the mixture was extracted with ether. The combined ether extracts were dried and evaporated to give the title compound. Yield: 0.63 g (89%).

B. 3- (4-Propylthio-1,2,5-thiadiazol-3-yl) -1-methyl-pyridinium iodide Methyl iodide (0.5 mL, 8 mmol) and 3- (4-propylthio-1, A mixture of 2,5-thiadiazol-3-yl) pyridine (0.63 g, 2.6 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours, then the mixture was evaporated.

C. 3- (4-Propylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (200 mg, 5 mmol) was added to a solution of 3- (4-propylthio-1,2,5-thiadiazol-3-yl) -1-methylpyridium iodide (2.6 mmol) in ethanol (99.9% , 15 ml). The reaction mixture was stirred at -10 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 35,310 mg (m.p. 138-139 ° C; M +: 255 compound 47).

54 95704

Example 45 A. 3- (4-Butylthio-1,2,5-thiadiazol-3-yl) pyridine

Sodium hydrogen sulfide (0.5 g, 6.8 mmol) was added at room temperature to a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) -5-pyridine (0.5 g, 2.5 mmol) in dimethylformamide. (20 mL), and the reaction mixture was stirred for 30 minutes. Potassium carbonate (2 g, 14.5 mmol) and butyl iodide (1 mL, 8.8 mmol) were added to the mixture and the reaction mixture was stirred for an additional 10 minutes. Water (50 ml) was added to the mixture, and the mixture was extracted with ether. The combined ether extracts were dried and evaporated to give the title compound. Yield: 0.6 g.

B. 3- (4-Butylthio-1,2,5-thiadiazol-3-yl) -1-methyl-pyridinium iodide Methyl iodide (1 mL, 15 mmol) was added 3- (4-butylthio-1,2, To a solution of 5-thiadiazol-3-yl) pyridine (0.6 g, 2.3 mmol), the reaction mixture was stirred at room temperature for 48 hours, then the mixture was evaporated.

C. 3- (4-Butylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (250 mg, 6.2 mmol) was added to a solution of 3- (4-butylthio-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (2.3 mmol) in ethanol (99.9%). , 20 ml) and the reaction mixture was stirred at 0 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 300 mg (m.p. 148-150 ° C; M +: 269 compound 48).

Example 46 A. 3- (4-Methylthio-1,2,5-thiadiazol-3-yl) pyridine

Sodium sulfide (0.5 g, 6.8 mmol) was added to a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) pyridin-35 (0.5 g, 2.5 mmol) at room temperature. in dimethylformamide 55 95704 (20 ml), and the reaction mixture was stirred for 30 minutes. Potassium carbonate (2 g, 14.5 mmol) and methyl iodide (1 mL, 15 mmol) were added to the mixture and the reaction mixture was stirred for an additional 10 minutes. Water (50 ml) was added to the mixture, and the mixture was extracted with ether. The combined ether extracts were dried and evaporated to give the title compound. Yield: 0.5 g.

B. 3- (4-Methylthio-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide Methyl iodide (1 mL, 15 mmol) was added as 3- (4-methylthio-1,2,5,5). -thiadiazol-3-yl) pyridine (0.5 g, 2.3 mmol), the reaction mixture was stirred at room temperature for 48 hours, then the mixture was evaporated.

C. 3- (4-Methylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (250 mg, 6.2 mmol) was added to a solution of 3- (4-methylthio-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (2.3 mmol) in ethanol (99.9%). , 20 ml) and the reaction mixture was stirred at 0 ° C for 1 hour.

The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated and the residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone. Yield: 300 mg (m.p. 169-170 ° C; M *: 227 compound 49).

Example 47 A. α-Oximino-3-pyridylacetonitrile 3-Pyridylacetonitrile (47.2 g, 400 mmol) was dissolved in a solution of sodium hydroxide (16 g, 400 mmol) in methanol (100 mL). Methyl nitrite, developed by dropwise addition of a mixture of concentrated sulfuric acid (12.8 mL) and water (26 mL) to a solution of sodium nitrite (33.2 g, 480 mmol) in a mixture of water (20 mL) and methanol (20 mL), was passed at 0 ° C. 3-pyridyyliasetonitriililiuokseen. The reaction mixture was stirred at 0 ° C for 1 hour, then the precipitate was collected by filtration. The precipitate was washed with a small amount of methanol to give the title compound. Yield: 41.1 g (70%), M +: 147.

B. α-Oximino-3-pyridylacetamidoxime A mixture of α-oximino-3-pyridylacetonitrile (41.0 g, 279 mmol), hydroxylamine hydrochloride (21.5 g, 310 mmol) and sodium acetate (50.8 g, 620 mmol) in ethanol. (99.9%, 500 mL) was refluxed for 4 hours. The mixture was cooled and the precipitate was collected by filtration and dried. The precipitate contained the desired product and sodium acetate (85 g, 168%); M *: 180.

C. 3- (4-Amino-1,2,5-oxadiazol-3-yl) pyridine Crude α-oximino-3-pyridylacetamidoxime (5 g) and phosphorus pentachloride (5 g) were heated in anhydrous ether (250 ml). 6 hours. Water and potassium carbonate were added to the alkaline pH and the phases were separated. The aqueous phase was extracted with ether and the combined ether phases were dried. Evaporation of the ether phases gave the title compound. Yield: 805 mg; M +: 162.

D. D. 3- (4-Amino-1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide 3- (4-amino-1,2,5-oxadiazol-3-yl) pyridine (870 mg, 5.3 mmol) in acetone (20 mL) was added methyl iodide (990 μΐ, 16 mmol) and the reaction mixture was stirred at room temperature overnight. The title compound precipitated and was collected by filtration. Yield: 1.1 g 69%).

E. 3- (4-Amino-1,2,5-oxadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (262 mg, 6.9 mmol) was added. At 3 ° C to a solution of 3- (4-amino-1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide (1.05 g, 3.45 mmol) in methanol (80 mL). After 15 minutes, water (40 ml) was added and the mixture was extracted with ether. The ether phase was dried, evaporated and the residue was purified by column chromatography 57 95704 (eluent: ethyl acetate / methanol 2: 1). Crystallization from acetone with oxalic acid gave 310 mg (50%) of the title compound (mp 181-183 ° C; M +: 180; compound 50). Example 48 5 A. 3- (4-Acetylamino-1,2,5-oxadiazol-3-yl) pyridine

The crude hydroxyimino-3-pyridylmethylaminooxime (4.5 g) and polyphosphoric acid (49 g) were stirred at 100 ° C for 18 hours. After the mixture was cooled to room temperature, aqueous ammonia (25%) was slowly added to a pH above 9 and the precipitate formed was filtered. The precipitate was dissolved in water and extracted with methylene chloride. The organic phases were combined, dried and evaporated to give the title compound. Yield: 430 mg.

B. 3- (4-Acetylamino-1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide

Methyl iodide (450 μΐ, 7.2 mmol) was added to a solution of 3- (4-acetylamino-1,2,5-oxadiazol-3-yl) pyridine (490 mg, 2.4 mmol) in acetone. The reaction mixture was stirred at 20 room temperature for 18 hours and the precipitated title compound was collected by filtration. Yield: 640 mg (77%).

C. 3- (4-Acetylamino-1,2,5-oxadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (140 mg, 3.7 mmol) was added at 0 ° C. in 3- (4-acetylamino-1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide (640 mg, 1.85 mmol) in methanol (15 mL). After 15 minutes, water (10 ml) was added and the mixture was extracted with ether. The ether phase was dried and evaporated. Crystallization of the residue from acetone with oxalic acid gave 140 mg of the title compound (m.p. 180-184 ° C; M +: 222; compound 51).

58 95704

Example 49 A. 3- (1,2,5-Oxadiazol-3-yl) pyridine and 3- (4-chloro-1,2,5-oxadiazol-3-yl) pyridine 3- (4-amino-1 To a solution of (2,5-oxadiazol-3-yl) pyridine 5 (1.0 g, 6.2 mmol) in a mixture of glacial acetic acid (16 mL) and concentrated hydrochloric acid (5.2 mL) at 0 ° C was added CuCl 2 ( 938 mg, 7 mmol) and copper wire (100 mg). After 10 minutes, a solution of sodium nitrite (483 mg, 7 mmol) in water (3 mL) was added dropwise at 5 ° C. The reaction mixture was stirred for an additional 30 minutes at 0 ° C. A 2N aqueous NaOH solution was added to the mixture to an alkaline pH, and the mixture was extracted with ether. The ether phases were dried and evaporated to give a mixture of the title compounds. They were separated by column chromatography (SiO 2, eluent: ethyl acetate) to give 230 mg of the chlorine compound (upper spot) and 60 mg of unsubstituted product (lower spot).

B. 3- (4-Chloro-1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide Methyl iodide (1 mL, 15 mmol) was added 3- (4-chloro-1,2, 5-oxadiazol-3-yl) pyridine (230 mg, 1.2 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 hours and the precipitated title compound was collected by filtration.

25 C. 3- (4-chloro-1,2,5-oxadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (119 mg, 3.2 mmol) was added at 0 ° C to a solution of 3- (4-chloro-1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide (1.2 mmol) in methanol ( 5 ml).

After 15 minutes, water was added and the mixture was extracted with ether. The ether phase was dried and evaporated. Crystallization of the residue from acetone with oxalic acid and recrystallization from acetone gave 60 mg of the title compound (m.p. 126-129 ° C; M *: 198 and 200; compound 52).

59 95704

Example 50 A. 3- (1,2,5-Oxadiazol-3-yl) -1-methylpyridinium iodide

Methyl iodide (1 mL, 15 nunol) was added to a solution of 3- (1,2,5-5 oxadiazol-3-yl) pyridine (430 mg, 2.9 mmol) in acetone (20 mL). The reaction mixture was stirred at room temperature for 18 hours and the precipitated title compound was collected by filtration. Yield: 700 mg (82%).

B. 3- (1,2,5-Oxadiazol-3-yl) -1,2,5,6-tetrahydro-1-10 methylpyridine oxalate

Sodium borohydride (168 mg, 4.4 mmol) was added at 0 ° C to a solution of 3- (1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide (640 mg, 2.2 mmol) in methanol (15 mL). ) and water (2 ml). After 15 minutes, water was added and the mixture was extracted with ether. The ether phase was dried and evaporated. Crystallization of the residue from acetone with oxalic acid gave 100 mg of the title compound (m.p. 238-240 ° C, dec.; M +: 165; compound 53).

Example 51 A. 3- (4-Hexyloxy-1,2,5-oxadiazol-3-yl) pyridine

To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol (10 mL) was added 3- (4-chloro-1,2,5-oxadiazol-3-yl) pyridine (180 mg, 1 mmol). The mixture was stirred at 25 ° C for 18 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4-Hexyloxy-1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and 3- (4-hexyloxy-1,2,5-oxadiazol-3-yl) pyridine (1 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours, then the mixture was evaporated. to give the title compound 35.

60 95704 C. 3- (4-Hexyloxy-1,2,5-oxadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (76 mg, 2 mmol) was added at 0 ° C to a solution of 3- (4-hexyloxy-1,2,5-oxadiazol-3-yl) -1-5 methylpyridinium iodide (1 mmol) in methanol (5 mL) and the reaction mixture. stirred at 0 ° C for 15 minutes. The mixture was evaporated and the residue was dissolved in water and extracted with ether. The ether phase was dried and evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 60 mg of the title compound (m.p. 143-147 ° C; M *: 265; compound 54).

Example 52 A. (3- (4-butyloxy-1,2,5-oxadiazol-3-yl) pyridine).

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (5 mL) was added 3- (4-chloro-1,2,5-oxadiazol-3-yl) -pyridine (350 mg, 1.9 mmol). ). The mixture was stirred at 25 ° C for 2 hours, then the mixture was evaporated. The residue was dissolved in water and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.

B. 3- (4-Butyloxy-1,2,5-oxadiazol-3-yl) -1-methylpyrididinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and 3- (4-butyloxy-1,2,5-oxadiazol-3-yl) pyridine (1.9 mmol) in acetone (10 ml) was stirred at room temperature for 18 hours, then the mixture was evaporated. to give the title compound 30.

C. 3- (4-Butyloxy-1,2,5-oxadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate 11

Sodium borohydride (148 mg, 3.8 mmol) was added to a solution of 3- (4-butyloxy-1,2,5-oxadiazol-3-yl) -1-methylpyrrolidinium 35-dinium iodide (1.9 mmol) in methanol (20 mL). ) and no 95704 reaction mixture was stirred at 0 ° C for 15 minutes. The mixture was evaporated and the residue was dissolved in water and extracted with ether. The ether phase was dried and evaporated and the residue was purified by column chromatography (SiO 2, eluent: 5: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 120 mg of the title compound (m.p. 132-135 ° C + M +: 237; compound 55).

Example 53 10 A. 3- (4- (3-Hexynyloxy) -1,2,5-oxadiazol-3-yl) pyridine 3-Hexyn-1-ol (980 mg, 10 mmol) and sodium hydride (240 mg, 10 mmol) in anhydrous tetrahydrofuran was added a solution of 3- (4-chloro-1,2,5-oxadiazol-3-15 yl) pyridine (450 mg, 2.5 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.

B. B. 3- (4- (3-Hexynyloxy) -1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide

A mixture of methyl iodide (1.5 mL, 22 mmol) and 3- (4- (3-hexynyloxy) -1,2,5-oxadiazol-3-yl) pyridine (2.5 mmol) in acetone (20 mL) was stirred. at room temperature for 18 hours, then the mixture was evaporated to give the title compound.

C. 3- (4- (3-Hexynyloxy) -1,2,5-oxadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of 3-30 (4- (3-hexynyloxy) -1,2,5-oxadiazol-3-yl) -1-methylpyridinium iodide (2.5 mmol) in methanol (20 mL). ) and the reaction mixture was stirred at 0 ° C for 15 minutes. The mixture was evaporated and the residue was dissolved in water and extracted with ether. The ether phase was dried and evaporated and the residue was purified by flash chromatography (SiO 2, eluent: 62: 70704 ti: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 50 mg of the title compound (m.p. 159-161 ° C; M *: 261; compound 56).

Example 54 3- (4-Pentyl-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridinium oxalate 3- (4-chloro-1,2,5 -thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (450 mg, 1.5 mmol) in a solution of tetrahydrofuran (20 mL) at 0 ° C was slowly added pentylmagnesium bromide (1, 5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 minutes, then water (20 ml) was added. The product was extracted with ether (3 x 100 ml), the ether product dried and evaporated. Residue 15 was crystallized as the oxalate salt from acetone to give 300 mg (58%) of product. It was recrystallized from ethanol to give 125 mg (24%) of the title compound (m.p. 156-157 ° C; M *: 251; compound 57).

Example 55 3- (4-Heptyl-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridinium oxalate 3- (4-chloro-1,2,5 -thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 mL) was slowly added at 0 ° C 25 heptylmagnesium bromide (1, 5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 minutes, then water (20 ml) was added. The product was extracted with ether (3 x 100 ml), the ether extract dried and evaporated. The residue was crystallized as the oxalate salt from acetone to give 30,400 mg (73%) of product (m.p. 151-152 ° C; M *: 274; compound 58).

63 95704

Example 56 3- (4- (5-Hexenyl) -1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridinium oxalate 3- (4-chloro-1,2,2 To a solution of 5-thiadiazol-3-yl) -1,2,5,6-tetra-5-hydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 mL) at 0 ° C was slowly added 5-hexenylmagnesium bromide. (1.5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 minutes, then water (20 ml) was added. The product was extracted with ether 10 (3 x 100 ml), the ether extract dried and evaporated.

The residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 340 mg (64%) of product (m.p. 113-115 ° C; M +: 263; compound 15 59).

Example 57 3- (4-Octyl-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridinium oxalate 3- (4-chloro-1,2,5- To a solution of thiadiazol-3-yl) -1,2,5,6-tetra-20-hydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 mL) at 0 ° C was slowly added octyl magnesium bromide (1.5 mL). mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 minutes, then water (20 ml) was added. The product was extracted with ether (3 x 100 ml), the ether extract dried and evaporated. The residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 430 mg (75%) of product (mp 157-158 ° C; M *: 293; compound 60).

Example 58 3- (4-Isobutyl-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridinium oxalate 3- (4-chloro-1,2,5-thiadiazole 3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (300 mg, 1.5 mmol) in a solution of tetrahydrofuran (20 mL) at 0 ° C was slowly added 64 95704 isobutylmagnesium bromide (1, 5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 minutes, then water (20 ml) was added. The product was extracted with ether (3 x 100 ml), the ether extract dried and evaporated. Residue 5 was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 350 mg (76%) of product (mp 148-149 ° C; M +: 237; compound 61). Example 59 3- (4-Cyclopropylmethyl-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridinium oxalate 3- (4-chloro-1,2,5-thiadiazole To a solution of 3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (300 mg, 1.4 mmol) in tetrahydrofuran (20 mL) at 0 ° C was slowly added cyclopropylmethylmagnesium bromide (1.5 mmol). ) solution in tetrahydrofuran. The reaction mixture was stirred for 10 minutes, then water (20 ml) was added. The product was extracted with ether (3 x 100 ml), the ether extract dried and evaporated. The residue was purified by flash chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 380 mg (83%) of product (mp 147-148 ° C; M *: 235; compound 62).

Example 60 3- (4-Propyl-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridinium oxalate 3- (4-chloro-1,2,5 -thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 mL) was slowly added at 0 ° C 30-propylmagnesium bromide (1.5 mL). mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 minutes, then water (20 ml) was added. The product was extracted with ether (3 x 100 ml), the ether extract dried and evaporated. The residue was crystallized as the oxalate salt from acetone to give 65 95704 350 mg (75%) of product (m.p. 141-142 ° C; M +: 223; compound 63).

Example 61 A. 3- (4-Octylthio-1,2,5-thiadiazol-3-yl) pyridine Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added at room temperature to 3- (4-chloro-1,2 To a solution of (5-thiadiazol-3-yl) -pyridine (0.59 g, 3 mmol) in dimethylformamide (20 mL), and the reaction mixture was stirred for 30 minutes. Potassium carbonate (1.24 g, 9 mmol) and 10 1-bromooctane (0.80 mL, 4.5 mmol) were added to the mixture and the reaction mixture was stirred for an additional 10 minutes. Water (50 ml) was added to the mixture, and the mixture was extracted with ether. The combined ether extracts were dried and evaporated to give the title compound.

B. 3- (4-Octylthio-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of 3- (4-octylthio-1,2,5-thiadiazol-3-yl) pyridine (3 mmol), the reaction mixture was stirred at room temperature for 48 hours, then the mixture was evaporated. .

C. 3- (4-Octylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (270 mg, 7 mmol) was added as 3- (4-octylthio To a solution of -1,2,5-thiadiazol-3-yl) -1-methylpyridin-25-iodine iodide (3 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C for 1 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was dried and evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 400 mg of the title compound (m.p. 121-122 ° C; M +: 325; compound 64).

66 95704

Example 62 A. 3- (4-Ethylthio-1,2,5-thiadiazol-3-yl) pyridine Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added at room temperature to 3- (4-chloro-1,2, To a solution of 5-thiadiazol-3-yl) -5-pyridine (0.59 g, 3 mmol) in dimethylformamide (20 mL), and the reaction mixture was stirred for 30 minutes. Potassium carbonate (1.24 g, 9 mmol) and 1-ethyl iodide (0.36 mL, 4.5 mmol) were added to the mixture and the reaction mixture was stirred for an additional 10 minutes. Water (10 ml) was added to the mixture, and the mixture was extracted with ether. The combined ether extracts were dried and evaporated to give the title compound.

B. 3- (4-Ethylthio-1,2,5-thiadiazol-3-yl) -1-methyl-pyridinium iodide Methyl iodide (0.5 mL, 7.5 mmol) was added to 3- (4-ethylthio-1, To a solution of 2,5-thiadiazol-3-yl) pyridine (3 mmol), the reaction mixture was stirred at room temperature for 48 hours, then the mixture was evaporated.

C. 3- (4-Ethylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (270 mg, 7 mmol) was added to a solution of 3- (4-ethylthio-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (3 mmol) in ethanol (99.9%, 20 mmol). ml) and the reaction mixture was stirred at 0 ° C for 1 hour. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was dried and evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 490 mg of the title compound (m.p. 145-146 ° C; M +: 241;

Example 63 A. 3- (4-Pentylthio-1,2,5-thiadiazol-3-yl) pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added at 35 room temperature to a solution of 3- (4-chloro-1,2,5-thiadiazol-3-yl) -6795704 pyridine (0.59 g, 3 mmol) in dimethylformamide. -sa (20 ml), and the reaction mixture was stirred for 30 minutes. Potassium carbonate (1.24 g, 9 mmol) and pentyl bromide (700 mg, 4.5 mmol) were added to the mixture, and the reaction mixture was stirred for an additional 10 minutes. Water (50 ml) was added to the mixture, and the mixture was extracted with ether. The combined ether extracts were dried and evaporated to give the title compound.

B. 3- (4-Pentylthio-1,2,5-thiadiazol-3-yl) -1-methylpyrididinium iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of 3- (4-pentylthio-1,2,5-thiadiazol-3-yl) pyridine (3 mmol), the reaction mixture was stirred at room temperature for 48 hours, then the mixture was evaporated.

15 C. 3- (4-Pentylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (300 mg, 8 mmol) was added 3- (4- pentylthio-1,2,5-thiadiazol-3-yl) -1-methylpyridinium iodide (3 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C for 1 h.

The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was dried and evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The Ot-25 title compound was crystallized as the oxalate salt from acetone to give 430 mg of the title compound (m.p. 136-138 ° C; M +: 283; compound 66).

Example 64 A. 3- (4-Hexylthio-1,2,5-thiadiazol-3-yl) pyridine Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added at room temperature to 3- (4-chloro-1,2 To a solution of (5-thiadiazol-3-yl) -pyridine (0.59 g, 3 mmol) in dimethylformamide (20 mL), and the reaction mixture was stirred for 30 minutes. Potassium carbonate (1.24 g, 9 mmol) and hexyl bromide (0.63 mL, 4.5 mmol) were added to the mixture, and the reaction mixture was stirred for an additional 10 minutes. Water (50 ml) was added to the mixture, and the mixture was extracted with ether. The combined ether extracts were dried and evaporated to give the title compound.

5 B. 3- (4-Hexylthio-1,2,5-thiadiazol-3-yl) -1-methyl-pyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of 3- (4-hexylthio-1,2,5-thiadiazol-3-yl) pyridine (3 mmol), the reaction mixture was stirred at room temperature for 48 hours, then the mixture was evaporated.

C. 3- (4-Hexylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine oxalate Sodium borohydride (230 mg, 6 mmol) was added to 3- (4-hexylthio). To a solution of -1,2,5-thiadiazol-3-yl) -1-methylpyridin-15-iodine iodide (3 mmol) in ethanol (99.9%, 20 mL) and the reaction mixture was stirred at 0 ° C for 1 h. The mixture was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was dried and evaporated and the residue was purified by column chromatography (SiO 2, eluent: ethyl acetate / methanol 4: 1). The title compound was crystallized as the oxalate salt from acetone to give 350 mg of the title compound (m.p. 126-127 ° C; M *: 297? Compound 67).

It is to be understood that the invention as shown and described is not limited to the precise details of the procedures or to the compounds, compositions, methods and processes described, as modifications and equivalent embodiments thereof will be apparent to those skilled in the art; the invention is thus limited only to the scope defined in the appended claims.

Claims (6)

69 95704 A process for the preparation of novel therapeutically useful substituted pyridine derivatives of formula 1 and pharmaceutically acceptable salts thereof having the formula R 1 Y> 10 (I) R wherein Z is oxygen or sulfur, R is hydrogen or C 1-15 alkyl and R 1 is halogen, amino, C 4-8 (cycloalkylalkyl), cyclopropylmethoxy, benzyloxy, morpholino, C 1-6 alkyl-substituted piperidino, C 1-6 acylamino, C 1-6 alkylamino, -O-R 2 or -S-R 2, wherein R 2 is straight-chain or branched C 1-6 alkyl, straight-chain or branched C 2-6 alkenyl, straight-chain or branched C 2-6 alkynyl, or R 2 is -R 3 -O-R 4 or -R 3 -O-R 4 -O-R 5, wherein R3, R4 and R5 independently of one another denote C1-4-alkyl, characterized in that the compound of formula 25R! Wherein R 1 and R 1 are as defined above, are alkylated with an alkyl halide and the resulting compound is reduced with hydride ions to give a compound of formula I wherein R is C 1-4 alkyl and, if desired, the resulting compound of formula I The compound of formula wherein R is C 1-3 alkyl is dealkylated to give a compound of formula I wherein R is hydrogen and / or, if desired, the resulting compound is converted into a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that 1,2,5,6-tetrahydro-1-methyl-3- (4-pentyloxy-1,2,5-thiadiazol-3-yl) pyridine is prepared. -ni or a pharmaceutically acceptable salt thereof. Process according to Claim 1, characterized in that 3- (4-hexyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine or a a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that 3- (4-butylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine or a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that 3- (4-pentylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine or a pharmaceutically acceptable salt thereof is prepared . Process according to Claim 1, characterized in that 3- (4-hexylthio-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine or a pharmaceutically acceptable salt. 7i 95704